Effectiveness and Drug Adherence in Rheumatoid Arthritis Patients on Biologic Monotherapy: A prospective observational study in Southern Sweden

Transcription

1 Effectiveness and Drug Adherence in Rheumatoid Arthritis Patients on Biologic Monotherapy: A prospective observational study in Southern Sweden Collaborators: Primary investigators Dr Lars Erik Kristensen, MD, Dr. Med; Rheumatologist Tanja Schjødt Jørgensen, MSc. Senior clinical supervisor Prof Henning Bliddal Ass Prof Carl Turesson Ass Prof Meliha Kapetanovic Dr Robin Christensen, MSc, PhD; Biostatistician Disclosure and role of the funding bodies: This project will be sponsored by Lund University and the Oak Foundation. The sponsors will have neither influence on the protocol, nor the acquisition, interpretation or publishing of data. Conflict of Interest:

2 OVERALL GOAL To evaluate and compare effectiveness and drug adherence of the currently available biological tumor necrosis factor inhibitor therapies applied as monotherapy in South Swedish patients with Rheumatoid Arthritis (RA). INTRODUCTION Rheumatoid arthritis (RA) patients should be treated as early as possible with disease-modifying antirheumatic drugs (DMARDs) to improve the disease course [1]. Methotrexate (MT) is considered the anchor drug in RA, both on the basis of its efficacy and safety as monotherapy, as well as its ability to increase the efficacy of biologic agents when used in combination [2, 3]. The American College of Rheumatology (ACR) recommends the use of an anti-tnf biologic with or without MT in patients who have high disease activity with poor prognostic features. Except for infliximab and golimumab, which should only be prescribed in combination with MT or other conventional (synthetic) DMARDs (csdmards), the other biologic DMARDs (bdmards) can be given either as monotherapy or in combination with MT [4]. It is estimated that between 10 and 30% of RA patients are MT-intolerant and discontinuation is common in clinical practice [5]. Adverse effects from MT include ulcerative stomatitis, leukopenia, liver toxicity, nausea and abdominal distress [6]. Thus, there are many reasons for discontinuation of MT during biologic therapy or initiating at least some of the biological agents as monotherapy. For those patients who require treatment with a biologic agent and cannot tolerate MT, biologic monotherapy may be a good option. Effectiveness and drug adherence of biologic monotherapy has previously been described in a cohort study of patients with RA registered in the Danish DANBIO registry (REF: DANBIO article). It has been well established that RA incurs a substantial socioeconomic burden [7] and this has recently been supported by the Global Burden of Disease studies [8, 9]. In this context, the cost-effectiveness of treating RA has been repeatedly addressed, and the impact of modern therapies on late, costly consequences of RA, such as joint replacement surgery, is noteworthy [10]. While rheumatologists cannot generally be held responsible for costs of treatment when attempting to provide best care in line with overarching principle A, this item does reiterate the responsibility of the rheumatologist to consider economic implications when selecting between treatment strategies or modalities with similar efficacy and safety in the short or intermediate term. Cost considerations by rheumatologists will become more important once biosimilar biological agents become available [11]. In parallel, payers (governments or social security agencies) ought to take the overall individual and societal implications of RA into account when making decisions on medical costs. However, little is known about utility gain in clinical practice. Moreover, reports from independent cohorts in a similar clinical setting are lacking.

3 Objective To describe the frequency and type of biologic drugs used in monotherapy in a south Swedish setting of patients with RA. Further, to evaluate and compare treatment efficacy with special focus on utility (EQ5D) and tolerability (drug adherence) among the different biologic therapies. Hypothesis A considerable gain in health utility when treating RA patients with biologic monotherapy is expected. A difference in drug survival is corresponding to modality of biologic treatment. Design: Data extracted from SSATG will be searched for cases of rheumatoid arthritis (patients treated) registered, from the period 2006 and through, as treated with any biologic without concomitant conventional synthetic DMARD (csdmard) therapy, defined as monotherapy. Only patients with primary monotherapy i.e., from baseline with the current biologics will be included. Primary, secondary outcomes and design variables Variable Baseline 3 months 6 months Comment (t=0 months) Female, no. (%) Age, years Disease duration, years Number of previous DMARDs Previous use of MT, no. (%) Concomitant prednisolone, no. (%) Biological therapy, name Outcome measures: EQ5D Swollen joint count, count: 0-28 Tender joint count, count: 0-28 C-reactive protein, mg/l Patient Pain, mm VAS Doctors global (5-grade Likert scale) Patient global assessment, mm

4 VAS Health assessment questionnaire (HAQ), score: 0-3 Composite outcome measures: ACR 20,50,70 Utility gain (delta EQ5D) Disease Activity Score in 28 joints (CRP) remission Primary outcome: Utility gain at 6month EQ5D Secondary outcomes (3&6 months data) EQ5D at 3 months ACR 20, 50, 70 treatment responses Drug survival DAS28 remission (<2.6) All dichotomous outcomes are given with and without LUNDE adjustment Statistical methods Descriptive statistics for continuous variables will be presented as medians and ranges; categorical variables will be presented as frequencies and percentages. Dichotomous outcomes will be compared using chi-square and continuous by Kruskal-Wallis test. ). Drug survival will be estimated according to Kaplan-Meier and further analyzed with log-rank statistics for comparing different treatments. Cox proportional hazard models were used to compare different drugs adjusting for potential confounding with a priori selected plausible covariates (age, gender, disease duration, HAQ, DAS28, CRP-level, number of previous DMARDs, and prednisolone adjustment for year of treatment initiation will be done using stratified cox-modeling). P- values less than 0.05 (two-sided) are considered statistically significant. Results and Publication strategy Proposed tables and figures (with reservation for changes) Table 1: Baseline characteristics of patients in the study population Table 2: EQ5D and treatment response after 3& 6 months of follow-up including LUNDE correction

5 Figure 1: Selection of patients (flow diagram) Figure 2: Drug adherence rate for each biological therapy. The number of withdrawals and the number of patients still receiving each drug at different time points are shown. Perspectives Rational use of pharmacotherapy in rheumatoid arthritis is prudent for the patient s quality of life, disablement, joint destruction, morbidity in general, and death. Given the success of the biologic therapies available in monotherapy compared to combination therapy with methotrexate or other csdmards, the patients could potentially benefit from a paradigm shift in the treatment strategy, excluding use of csdmards that cause a significant amount of side effects to the individual patients. Decision and policy makers need a transparent evidence base from various independent cohorts with different aspects of outcome (i.e., utility scores) Registration Protocol April1 st 2014 Data extraction and analysis May-September 2014 Drafting and circulation August-October 2014 Submission (target journal rheumatology Oxford) November 2014 References 1 Smolen JS, Aletaha D, Koeller M, et al. New therapies for treatment of rheumatoid arthritis. Lancet 2007;370: Nixon RM, Bansback N, Brennan A. Using mixed treatment comparisons and meta-regression to perform indirect comparisons to estimate the efficacy of biologic treatments in rheumatoid arthritis. Stat Med 2007;26:

6 3 Lie E, van der Heijde D, Uhlig T, et al. Treatment strategies in patients with rheumatoid arthritis for whom methotrexate monotherapy has failed: data from the NOR-DMARD register. Ann Rheum Dis 2011;70: Singh JA, Furst DE, Bharat A, et al update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken ) 2012;64: Yazici Y, Shi N, John A. Utilization of biologic agents in rheumatoid arthritis in the United States: analysis of prescribing patterns in 16,752 newly diagnosed patients and patients new to biologic therapy. Bull NYU Hosp Jt Dis 2008;66: Salliot C and van der HD. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis 2009;68: Lundkvist J, Kastang F, Kobelt G. The burden of rheumatoid arthritis and access to treatment: health burden and costs. Eur J Health Econ 2008;8 Suppl 2:S49-S60. 8 Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, : a systematic analysis for the Global Burden of Disease Study Lancet 2012;380: Vos T, Flaxman AD, Naghavi M, et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries : a systematic analysis for the Global Burden of Disease Study Lancet 2012;380:

7 10 Kobelt G and Jonsson B. The burden of rheumatoid arthritis and access to treatment: outcome and cost-utility of treatments. Eur J Health Econ 2008;8 Suppl 2: Dorner T, Strand V, Castaneda-Hernandez G, et al. The role of biosimilars in the treatment of rheumatic diseases. Ann Rheum Dis 2013;72:322-8.